白细胞介素-10 缺乏症加剧炎症诱导的 tau 病理。
Interleukin-10 deficiency exacerbates inflammation-induced tau pathology.
机构信息
Department of Molecular Genetics and Microbiology, University of New Mexico, MSC08 4660, 1 University of New Mexico, Albuquerque, NM, 87131, USA.
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
出版信息
J Neuroinflammation. 2021 Jul 18;18(1):161. doi: 10.1186/s12974-021-02211-1.
BACKGROUND
The presence of hyperphosphorylated microtubule-associated protein tau is strongly correlated with cognitive decline and neuroinflammation in Alzheimer's disease and related tauopathies. However, the role of inflammation and anti-inflammatory interventions in tauopathies is unclear. Our goal was to determine if removing anti-inflammatory interleukin-10 (IL-10) during an acute inflammatory challenge has any effect on neuronal tau pathology.
METHODS
We induce systemic inflammation in Il10-deficient (Il10) versus Il10 (Non-Tg) control mice using a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) to examine microglial activation and abnormal hyperphosphorylation of endogenous mouse tau protein. Tau phosphorylation was quantified by Western blotting and immunohistochemistry. Microglial morphology was quantified by skeleton analysis. Cytokine expression was determined by multiplex electro chemiluminescent immunoassay (MECI) from Meso Scale Discovery (MSD).
RESULTS
Our findings show that genetic deletion of Il10 promotes enhanced neuroinflammation and tau phosphorylation. First, LPS-induced tau hyperphosphorylation was significantly increased in Il10 mice compared to controls. Second, LPS-treated Il10 mice showed signs of neurodegeneration. Third, LPS-treated Il10 mice showed robust IL-6 upregulation and direct treatment of primary neurons with IL-6 resulted in tau hyperphosphorylation on Ser396/Ser404 site.
CONCLUSIONS
These data support that loss of IL-10 activates microglia, enhances IL-6, and leads to hyperphosphorylation of tau on AD-relevant epitopes in response to acute systemic inflammation.
背景
在阿尔茨海默病和相关的 tau 病中，过度磷酸化的微管相关蛋白 tau 的存在与认知能力下降和神经炎症密切相关。然而，炎症和抗炎干预在 tau 病中的作用尚不清楚。我们的目标是确定在急性炎症挑战期间去除抗炎性白细胞介素-10（IL-10）是否对神经元 tau 病理学有任何影响。
方法
我们使用单次腹腔（i.p.）注射脂多糖（LPS）在 Il10 缺陷（Il10）与 Il10（非 Tg）对照小鼠中诱导全身性炎症，以检查小胶质细胞活化和内源性小鼠 tau 蛋白的异常过度磷酸化。通过 Western blot 和免疫组织化学定量 tau 磷酸化。通过骨架分析定量小胶质细胞形态。通过 Meso Scale Discovery（MSD）的多重电化学发光免疫分析（MECI）确定细胞因子表达。
结果
我们的研究结果表明，Il10 的基因缺失促进了神经炎症和 tau 磷酸化的增强。首先，与对照组相比，LPS 诱导的 tau 过度磷酸化在 Il10 小鼠中显著增加。其次，LPS 处理的 Il10 小鼠表现出神经退行性病变的迹象。第三，LPS 处理的 Il10 小鼠表现出强大的 IL-6 上调，并且直接用 IL-6 处理原代神经元导致 tau 在 AD 相关表位上的 Ser396/Ser404 位点过度磷酸化。
结论
这些数据支持 IL-10 的缺失激活小胶质细胞，增强 IL-6，并导致急性全身性炎症时 tau 在 AD 相关表位上的过度磷酸化。
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